Matrix Gla protein deficiency causes arteriovenous malformations in mice
Yucheng Yao, … , Anthony Wang, Kristina I. Boström
Yucheng Yao, … , Anthony Wang, Kristina I. Boström
Published July 18, 2011
Citation Information: J Clin Invest. 2011;121(8):2993-3004. https://doi.org/10.1172/JCI57567.
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Research Article Vascular biology

Matrix Gla protein deficiency causes arteriovenous malformations in mice

Abstract

Arteriovenous malformations (AVMs) in organs, such as the lungs, intestine, and brain, are characteristic of hereditary hemorrhagic telangiectasia (HHT), a disease caused by mutations in activin-like kinase receptor 1 (ALK1), which is an essential receptor in angiogenesis, or endoglin. Matrix Gla protein (MGP) is an antagonist of BMPs that is highly expressed in lungs and kidneys and is regulated by ALK1. The objective of this study was to determine the role of MGP in the vasculature of the lungs and kidneys. We found that Mgp gene deletion in mice caused striking AVMs in lungs and kidneys, where overall small organ size contrasted with greatly increased vascularization. Mechanistically, MGP deficiency increased BMP activity in lungs. In cultured lung epithelial cells, BMP-4 induced VEGF expression through induction of ALK1, ALK2, and ALK5. The VEGF secretion induced by BMP-4 in Mgp–/– epithelial cells stimulated proliferation of ECs. However, BMP-4 inhibited proliferation of lung epithelial cells, consistent with the increase in pulmonary vasculature at the expense of lung tissue in the Mgp-null mice. Similarly, BMP signaling and VEGF expression were increased in Mgp–/– mouse kidneys. We therefore conclude that Mgp gene deletion is what we believe to be a previously unidentified cause of AVMs. Because lack of MGP also causes arterial calcification, our findings demonstrate that the same gene defect has drastically different effects on distinct vascular beds.

Authors

Yucheng Yao, Medet Jumabay, Anthony Wang, Kristina I. Boström

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Figure 1

MGP levels influence pulmonary vascular development.

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MGP levels influence pulmonary vascular development. (A) Photographs of ...
(A) Photographs of lungs and micro CT images of the pulmonary vasculature from Mgptg/wt, Mgp+/+, and Mgp–/– mice. Data are from a single experiment but are representative of 3 repeat experiments. Stars represent visualized pulmonary veins. See Supplemental Videos 1–3 for full 3D reconstruction of the pulmonary vasculature. Microfil compound was used for organ perfusion in order to visualize the vasculature. (B) Expression of vWF in lung sections from Mgptg/wt, Mgp+/+, and Mgp–/– mice, as determined by immunofluorescence (n = 3). Arrowheads indicate vWF-positive endothelium. (C) Presence of pulmonary arteriovenous shunts, as shown by UV-fluorescent microsphere passage. The microspheres bypassed the lungs in the Mgp–/– mice. BF, bright field. (D) Niduses of enlarged and tortuous blood vessels in Mgp–/– lung (left panels). Direct arteriovenous (AV) connections on the surface of a Mgp–/– lung (right panel). (E) Vessel density in lungs from Mgptg/wt, Mgp+/+, and Mgp–/– mice (n = 6). The left panel shows total vessel density, and the right panel shows vessel density of vessels with a caliber of less than 20 μm and more than 20 μm. (F) Expression of PECAM-1 and Ephrin B2 in lung tissues from Mgptg/wt, Mgp+/+, and Mgp–/– mice, as determined by real-time PCR and immunoblotting. Asterisks indicate statistically significant differences compared with wild-type (Mgp+/+). **P < 0.01, ***P < 0.001, Tukey’s test. Scale bars: 2 mm (A, rows 1–3, and C); 500 μm (A, row 4, and D, left and middle); 100 μm (B and D, right).